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1.  Differential effects of ischemic vascular disease and Alzheimer’s disease on brain atrophy and cognition 
We previously reported that pathologic measures of arteriosclerosis (AS), cerebral infarction, and Alzheimer’s disease (AD) are independently correlated with cortical gray matter (CGM) atrophy measured by in vivo magnetic resonance imaging (MRI). Here, we use path analyses to model the associations between these three pathology measures and cognitive impairment, as mediated by CGM atrophy, after controlling for age and education. In this sample of 116 elderly persons followed longitudinally to autopsy (ischemic vascular disease (IVD) program project), differential patterns were observed between AS and atrophy/cognition versus AD and atrophy/cognition. The total effect of AD pathology on global cognition (β = −0.61, s.e. = 0.06) was four times stronger than that of AS (β = −0.15, s.e. = 0.08). The effect of AS on cognition appears to occur through cerebral infarction and CGM atrophy (β = −0.13, s.e. = 0.04). In contrast, the effects of AD pathology on global cognition (β = −0.50, s.e. = 0.07) occur through a direct pathway that is five times stronger than the indirect pathway acting through CGM atrophy (β = −0.09, s.e. = 0.03). The strength of this direct AD pathway was not significantly mitigated by adding hippocampal volume to the model. AD pathology affects cognition not only through brain atrophy, but also via an unmeasured pathway that could be related to synaptic dysfunction before the development of cortical atrophy.
PMCID: PMC4758550  PMID: 26126864
Alzheimer’s; brain imaging; cerebrovascular disease; cognition
2.  Electrocardiographic Markers and the Left Ventricular Ejection Fraction have Cumulative Effects on Risk of Sudden Cardiac Death 
JACC. Clinical electrophysiology  2015;1(6):542-550.
To assess potential improvement in SCD risk prediction by adding selected risk markers from the 12-lead ECG to measurement of the left ventricular ejection fraction (LVEF).
Novel strategies to improve risk stratification for sudden cardiac death (SCD) are needed. Given the modest odds associated with most individual risk markers, combining multiple markers may be a useful approach.
From the ongoing Oregon Sudden Unexpected Death Study, SCD cases with pre-event LVEF available were compared to matched control subjects with coronary artery disease. Resting heart rate, QRS duration (QRSD), and JTc intervals were measured from archived ECGs prior and unrelated to the SCD event. Independent odds of SCD for individual and combined ECG markers were calculated.
SCD cases (n= 317; 67.9 ± 12.9 years) were more likely than controls (n=317; 67.9 ± 12.8 years) to have LVEF ≤ 35% (26% vs. 11%). Mean heart rate, QRSD, and JTc were significantly higher in cases (all p<0.0001). In adjusted analyses, higher heart rate [OR 2.6 (1.8 – 3.7)], QRSD [OR 1.5 (1.0 – 2.5)] and JTc [OR 2.3 (1.6 – 3.4)] were independently associated with SCD. When ECG markers were combined, SCD odds progressively increased with one [OR 3.4 (2.1 – 5.4)] and ≥ 2 elevated markers [OR 6.3 (3.3 – 12.1)]. Addition of ECG markers to an adjusted model with LVEF improved discrimination (C statistic 0.724 vs. 0.642) and net reclassification (by 22.7%) (p<0.0001).
Combining selected 12-lead ECG markers with LVEF improves SCD risk prediction, and warrants further investigation in prospective studies.
PMCID: PMC4776651  PMID: 26949741
sudden cardiac death; risk; electrocardiogram; ejection fraction
3.  Enhancement of viral escape in HIV-1 Nef by STEP vaccination 
AIDS (London, England)  2016;30(16):2449-2458.
Properly priming cytotoxic T-lymphocyte (CTL) responses is an important task in HIV-1 vaccination. However, the STEP trial showed no efficacy even though the vaccine elicited HIV-specific CTL responses. Our study is to investigate whether or not the STEP vaccine enhanced viral escape in infected volunteers.
The signature of viral escape, the presence of multiple escape variants, could be falsely represented by the existence of multiple founder viruses. Therefore, we use a mathematical model to designate STEP study patients with infections from a single founder virus. We then conduct permutation tests on each of 9988 Gag, Pol, and Nef overlapping peptides to identify epitopes with significant differences in diversity between the vaccine and placebo groups using previously published STEP trial sequence data.
We identify signatures of vaccine-enhanced viral escape within HIV-1 Nef from the STEP trial. Vaccine-treated patients showed a greater level of epitope diversity in one of the immunodomiant epitopes, EVGFPVRPQVPL (Nef65–76), compared with placebo-treated patients (P = 0.0038). In the other three Nef epitopes, there is a marginally significant difference in the epitope diversity between the vaccine and placebo group (P < 0.1). This greater epitope diversity was neither due to any difference in infection duration nor overall nef gene diversity between the two groups, suggesting that the increase in viral escape was likely mediated by vaccine-induced T-cell responses.
Viral escape in Nef is elevated preferentially in STEP vaccine-treated individuals, suggesting that vaccination primarily modulated initial CTL responses. Our observations provide important insights into improving vaccine-primed first immune control.
PMCID: PMC5051524  PMID: 27427874
HIV-1; Nef; vaccine; viral escape
4.  Vascular Effects of Early versus Late Postmenopausal Treatment with Estradiol 
The New England journal of medicine  2016;374(13):1221-1231.
Data suggest that estrogen-containing hormone therapy is associated with beneficial effects with regard to cardiovascular disease when the therapy is initiated temporally close to menopause but not when it is initiated later. However, the hypothesis that the cardiovascular effects of postmenopausal hormone therapy vary with the timing of therapy initiation (the hormone-timing hypothesis) has not been tested.
A total of 643 healthy postmenopausal women were stratified according to time since menopause (<6 years [early postmenopause] or ≥10 years [late postmenopause]) and were randomly assigned to receive either oral 17β-estradiol (1 mg per day, plus progesterone [45 mg] vaginal gel administered sequentially [i.e., once daily for 10 days of each 30-day cycle] for women with a uterus) or placebo (plus sequential placebo vaginal gel for women with a uterus). The primary outcome was the rate of change in carotid-artery intima– media thickness (CIMT), which was measured every 6 months. Secondary outcomes included an assessment of coronary atherosclerosis by cardiac computed tomography (CT), which was performed when participants completed the randomly assigned regimen.
After a median of 5 years, the effect of estradiol, with or without progesterone, on CIMT progression differed between the early and late postmenopause strata (P = 0.007 for the interaction). Among women who were less than 6 years past menopause at the time of randomization, the mean CIMT increased by 0.0078 mm per year in the placebo group versus 0.0044 mm per year in the estradiol group (P = 0.008). Among women who were 10 or more years past menopause at the time of randomization, the rates of CIMT progression in the placebo and estradiol groups were similar (0.0088 and 0.0100 mm per year, respectively; P = 0.29). CT measures of coronary-artery calcium, total stenosis, and plaque did not differ significantly between the placebo group and the estradiol group in either postmenopause stratum.
Oral estradiol therapy was associated with less progression of subclinical atherosclerosis (measured as CIMT) than was placebo when therapy was initiated within 6 years after menopause but not when it was initiated 10 or more years after menopause. Estradiol had no significant effect on cardiac CT measures of atherosclerosis in either postmenopause stratum. (Funded by the National Institute on Aging, National Institutes of Health; ELITE number, NCT00114517.)
PMCID: PMC4921205  PMID: 27028912
5.  HIV Infection Is Associated With Progression of Subclinical Carotid Atherosclerosis 
Human immunodeficiency virus (HIV) infection was associated with greater increases in focal carotid artery plaque over 7 years among both women and men, particularly among those with lower CD4+ counts. Increased plaque was observed even among HIV-infected individuals with persistent virologic suppression.
Background. Individuals infected with human immunodeficiency virus (HIV) live longer as a result of effective treatment, but long-term consequences of infection, treatment, and immunological dysfunction are poorly understood.
Methods. We prospectively examined 1011 women (74% HIV-infected) in the Women's Interagency HIV Study and 811 men (65% HIV-infected) in the Multicenter AIDS Cohort Study who underwent repeated B-mode carotid artery ultrasound imaging in 2004–2013. Outcomes included changes in right common carotid artery intima-media thickness (CCA-IMT) and new focal carotid artery plaque formation (IMT >1.5 mm) over median 7 years. We assessed the association between HIV serostatus and progression of subclinical atherosclerosis, adjusting for demographic, behavioral, and cardiometabolic risk factors.
Results. Unadjusted mean CCA-IMT increased (725 to 752 µm in women, 757 to 790 µm in men), but CCA-IMT progression did not differ by HIV serostatus, either in combined or sex-specific analyses. Focal plaque prevalence increased from 8% to 15% in women and 25% to 34% in men over 7 years. HIV-infected individuals had 1.6-fold greater risk of new plaque formation compared with HIV-uninfected individuals (relative risk [RR] 1.61, 95% CI, 1.12–2.32), adjusting for cardiometabolic factors; the association was similar by sex. Increased plaque occurred even among persistently virologically suppressed HIV-infected individuals compared with uninfected individuals (RR 1.56, 95% CI, 1.07–2.27). HIV-infected individuals with baseline CD4+ ≥500 cells/µL had plaque risk not statistically different from uninfected individuals.
Conclusions. HIV infection is associated with greater increases in focal plaque among women and men, potentially mediated by factors associated with immunodeficiency or HIV replication at levels below current limits of detection.
PMCID: PMC4607734  PMID: 25904369
HIV infection; cardiovascular disease; atherosclerosis; intima-media thickness; viral load
6.  Antiretroviral Therapy Modifies the Genetic Effect of Known Type 2 Diabetes-Associated Risk Variants in the Women’s Interagency HIV Study 
AIDS (London, England)  2014;28(12):1815-1823.
Type 2 diabetes (DM) incidence is increased in HIV-infected persons. We examined the associations of DM with known DM-risk alleles from the general population in the context of HIV infection and explored effect modification by combination antiretroviral treatment (cART).
The Women’s Interagency HIV Study (WIHS) is a prospective cohort of HIV-infected women. Seventeen European-derived DM-risk polymorphisms were genotyped in eligible WIHS participants. Analyses were run separately for non-African-Americans (Whites, Hispanics, Asians, and other; n=378, 49 with incident DM) and African-Americans (n=591, 49 with incident DM). Cox proportional hazards models were fit to estimate hazard ratios (HRs) for DM overall and within strata of cART.
In non-African-Americans, heterogeneity across cART regimen was observed for 9 of 14 polymorphisms (phet<0.05). One polymorphism was statistically significantly inversely associated with DM risk among women taking 2 NRTIs+NNRTI. Five polymorphisms were statistically significantly associated with DM among women treated with ≥2 NRTIs + ≥1 PI and one polymorphism was associated with DM among those treated with ≥3 NRTIs ± NNRTI. The HR per risk allele for IGF2BP2 rs1470579 was 2.67 (95% CI 1.67–4.31) for women taking cART with ≥2 NRTIs+≥1 PI and 2.45 (95% CI 1.08–5.53) in women taking ≥3 NRTIs±NNRTI (phet=2.50×10−3). No such associations were observed in African-Americans.
Genetic susceptibility to DM, based on the variants studied, is substantially elevated among HIV-infected women using cART containing three or more NRTI/PI components. A personalized medicine approach to cART selection may be indicated for HIV-infected persons carrying these DM-risk variants.
PMCID: PMC4269472  PMID: 24932614
type 2 diabetes; genetics; HIV; women; antiretroviral therapy
7.  The Perimenopausal Aging Transition in the Female Rat Brain: Decline in Bioenergetic Systems and Synaptic Plasticity 
Neurobiology of aging  2015;36(7):2282-2295.
The perimenopause is an aging transition unique to the female that leads to reproductive senescence which can be characterized by multiple neurological symptoms. To better understand potential underlying mechanisms of neurological symptoms of perimenopause, the current study determined genomic, biochemical, brain metabolic and electrophysiological transformations that occur during this transition using a rat model recapitulating fundamental characteristics of the human perimenopause. Gene expression analyses indicated two distinct aging programs: chronological and endocrine. A critical period emerged during the endocrine transition from regular to irregular cycling characterized by decline in bioenergetic gene expression, confirmed by deficits in FDG-PET brain metabolism, mitochondrial function, and long-term potentiation. Bioinformatic analysis predicted insulin/IGF1 and AMPK/PGC1α signaling pathways as upstream regulators. Onset of acyclicity was accompanied by a rise in genes required for fatty acid metabolism, inflammation, and mitochondrial function. Subsequent chronological aging resulted in decline of genes required for mitochondrial function and β-amyloid degradation. Emergence of glucose hypometabolism and impaired synaptic function in brain provide plausible mechanisms of neurological symptoms of perimenopause and may be predictive of later life vulnerability to hypometabolic conditions such as Alzheimer’s.
PMCID: PMC4416218  PMID: 25921624
Perimenopause; Female brain aging; Glucose metabolism; Mitochondria; Synaptic plasticity; Hypometabolism; Fatty acid metabolism; Long-term potentiation
8.  The effect of APOE genotype on the delivery of DHA to cerebrospinal fluid in Alzheimer’s disease 
Apolipoprotein E (APOE) ɛ4 and low cerebrospinal fluid (CSF) amyloid-β42 (Aβ42) levels are predictors for developing Alzheimer’s disease (AD). The results of several studies indicate an interaction between docosahexaenoic acid (DHA) consumption and cognitive outcomes by APOE genotype. Our objective in the present study was to examine whether APOE ɛ4 genotype and low CSF Aβ42 levels were associated with reduced delivery of DHA to CSF in the Alzheimer’s Disease Cooperative Study-sponsored DHA clinical trial.
Phospholipid DHA was assayed in the plasma of 384 participants and CSF of 70 participants at baseline. Forty-four of the 70 participants completed the 18-month follow-up visit after allocation to placebo (n = 15) or DHA (n = 29). Plasma and CSF DHA levels, CSF Aβ42, Tau, and phosphorylated Tau were measured at baseline and after the 18-month intervention. Participants were divided into tertiles based on baseline Aβ42 CSF levels. To assess DHA delivery across the blood-brain barrier, the ratio of CSF to plasma DHA levels was calculated.
At baseline, there were no significant differences between CSF or plasma phospholipid DHA levels by CSF Aβ42 tertiles or ɛ4 status. After 18 months of DHA supplementation, participants at the lowest Aβ42 tertile had significantly lower CSF DHA levels (p = 0.01) and lower CSF-to-plasma DHA ratios (p = 0.05) compared to the other tertiles. Baseline CSF Aβ42 levels were significantly lower in ɛ4 carriers than in ɛ4 noncarriers (p = 0.01). Participants carrying the ɛ4 allele (n = 25) demonstrated a less pronounced increase in CSF DHA level compared with noncarriers (n = 4), with a possible interaction effect between treatment and APOE genotype (p = 0.07).
APOE ɛ4 allele and lower CSF Aβ42 levels were associated with less transport of DHA to CSF. Brain amyloid pathology may limit the delivery of DHA to the brain in AD.
Trial Registration identifier: NCT00440050. Registered on 22 Feb 2007.
PMCID: PMC4928349  PMID: 27358067
APOE; Alzheimer’s disease; Cerebrospinal fluid; Amyloid
9.  Associations of Urine Excretion of Isoflavonoids with Cognition in Postmenopausal Women in the Women’s Isoflavone Soy Health Clinical Trial 
Results from randomized trials of soy supplements on cognition in postmenopausal women are equivocal. We sought to determine associations of change in urine excretion of isoflavonoids on cognitive change.
Post hoc analysis of isoflavonoid exposures (mean 2.7 years) during the randomized, placebo-controlled, double-blind Women’s Isoflavone Soy Health trial.
General community.
350 healthy postmenopausal women.
25 g of isoflavone-rich soy protein (91 mg of aglycone weight isoflavones: 52 mg genistein, 36 mg daidzein, 3 mg glycitein) or milk protein-matched placebo, provided daily.
Overnight urine excretion and fasting plasma levels of isoflavonoids, and cognitive function, measured at baseline and endpoint.
300 women (mean age = 61 years, range 45-92 years) completed both cognitive assessments and did not use hormone replacement therapy during the trial. Mean on-trial change from baseline in urine excretion of isoflavonoids was not significantly associated with change in a composite score of global cognition (p=0.39). Secondary analyses indicated that change in urine excretion of isoflavonoids was inversely associated with change in a factor score representing general intelligence (p=0.02), but not with factor scores representing verbal or visual episodic memory. Mean differences in this general intelligence factor score among women in the first compared to highest quartile of isoflavonoid change are equivalent to an approximate 4.4 year age-associated decline. Analyses based on plasma isoflavonoid levels yielded similar but attenuated results.
Among healthy postmenopausal women, long-term changes in isoflavonoids are not associated with global cognition, supporting clinical trial results. Increasing isoflavonoid exposure from dietary supplements is, however, associated with decrements in general intelligence but not memory; this finding requires confirmation in future studies.
PMCID: PMC4226524  PMID: 24617349
Cognition; isoflavones; menopause; soy; women’s health
10.  Molecular clock of HIV-1 envelope genes under early immune selection 
Retrovirology  2016;13:38.
The molecular clock hypothesis that genes or proteins evolve at a constant rate is a key tool to reveal phylogenetic relationships among species. Using the molecular clock, we can trace an infection back to transmission using HIV-1 sequences from a single time point. Whether or not a strict molecular clock applies to HIV-1’s early evolution in the presence of immune selection has not yet been fully examined.
We identified molecular clock signatures from 1587 previously published HIV-1 full envelope gene sequences obtained since acute infection in 15 subjects. Each subject’s sequence diversity linearly increased during the first 150 days post infection, with rates ranging from \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$1.54 \times 10^{ - 5}$$\end{document}1.54×10-5 to \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$3.91 \times 10^{ - 5}$$\end{document}3.91×10-5 with a mean of \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$2.69 \times 10^{ - 5}$$\end{document}2.69×10-5 per base per day. The rate of diversification for 12 out of the 15 subjects was comparable to the neutral evolution rate. While temporal diversification was consistent with evolution patterns in the absence of selection, mutations from the founder virus were highly clustered on statistically identified selection sites, which diversified more than 65 times faster than non-selection sites. By mathematically quantifying deviations from the molecular clock under various selection scenarios, we demonstrate that the deviation from a constant clock becomes negligible as multiple escape lineages emerge. The most recent common ancestor of a virus pair from distinct escape lineages is most likely the transmitted founder virus, indicating that HIV-1 molecular dating is feasible even after the founder viruses are no longer detectable.
The ability of HIV-1 to escape from immune surveillance in many different directions is the driving force of molecular clock persistence. This finding advances our understanding of the robustness of HIV-1’s molecular clock under immune selection, implying the potential for molecular dating.
Electronic supplementary material
The online version of this article (doi:10.1186/s12977-016-0269-6) contains supplementary material, which is available to authorized users.
PMCID: PMC4888660  PMID: 27246201
HIV-1; Envelope gene; Molecular clock; Mathematical model
Menopause (New York, N.Y.)  2015;22(4):391-401.
To present methods and baseline data from the Early versus Late Intervention Trial with Estradiol (ELITE), the only clinical trial designed to specifically test the timing hypothesis of postmenopausal hormone therapy (HT). The timing hypothesis posits that HT effects depend on the temporal initiation of HT relative to time-since-menopause.
ELITE is a randomized, double-blinded, placebo-controlled trial with a 2x2 factorial design. 643 healthy postmenopausal women without cardiovascular disease were randomized to oral estradiol or placebo for up to 6-7 years according to number of years-since-menopause, <6 years or ≥10 years. Carotid artery intima-media thickness (CIMT) and cardiac computed tomography were conducted to determine HT effects on subclinical atherosclerosis across menopause strata.
Participants in the early and late postmenopausal strata were well-separated by mean age, 55.4 versus 65.4 years and median time-since-menopause, 3.5 versus 14.3 years, respectively. The expected risk factors were associated with CIMT at baseline in both strata (age, blood pressure and body mass index). In the early but not in the late postmenopausal group, there were significant associations between CIMT and factors that may play a role in responsiveness of atherosclerosis progression according to timing of HT initiation. These include LDL-C, HDLC, sex hormone binding globulin and serum total estradiol.
The ELITE randomized controlled trial is timely and unique. Baseline data indicate that ELITE is well-positioned to test the HT timing hypothesis in relation to atherosclerosis progression and coronary artery disease. (NCT00114517;
PMCID: PMC4376597  PMID: 25380275
menopause; postmenopause; women; hormone therapy; estrogen; randomized trials; cardiovascular disease; cognition; timing hypothesis
13.  Prenatal Air Pollution Exposure and Early Cardiovascular Phenotypes in Young Adults 
PLoS ONE  2016;11(3):e0150825.
Exposure to ambient air pollutants increases risk for adverse cardiovascular health outcomes in adults. We aimed to evaluate the contribution of prenatal air pollutant exposure to cardiovascular health, which has not been thoroughly evaluated. The Testing Responses on Youth (TROY) study consists of 768 college students recruited from the University of Southern California in 2007–2009. Participants attended one study visit during which blood pressure, heart rate and carotid artery arterial stiffness (CAS) and carotid artery intima-media thickness (CIMT) were assessed. Prenatal residential addresses were geocoded and used to assign prenatal and postnatal air pollutant exposure estimates using the U.S. Environmental Protection Agency’s Air Quality System (AQS) database. The associations between CAS, CIMT and air pollutants were assessed using linear regression analysis. Prenatal PM10 and PM2.5 exposures were associated with increased CAS. For example, a 2 SD increase in prenatal PM2.5 was associated with CAS indices, including a 5% increase (β = 1.05, 95% CI 1.00–1.10) in carotid stiffness index beta, a 5% increase (β = 1.05, 95% CI 1.01–1.10) in Young’s elastic modulus and a 5% decrease (β = 0.95, 95% CI 0.91–0.99) in distensibility. Mutually adjusted models of pre- and postnatal PM2.5 further suggested the prenatal exposure was most relevant exposure period for CAS. No associations were observed for CIMT. In conclusion, prenatal exposure to elevated air pollutants may increase carotid arterial stiffness in a young adult population of college students. Efforts aimed at limiting prenatal exposures are important public health goals.
PMCID: PMC4780745  PMID: 26950592
14.  Abnormal blood rheology and chronic low grade inflammation: possible risk factors for accelerated atherosclerosis and coronary artery disease in Lewis negative subjects 
Atherosclerosis  2015;239(1):248-251.
To test the hypothesis that abnormal hemorheology and chronic low-grade inflammation are more prevalent in Lewis negative individuals, possibly contributing to premature atherosclerosis.
Methods and Results
We enrolled 223 healthy subjects (154 females, mean age: 64yrs). Conventional risk factors, markers of inflammation and hemorheological profiles were measured; Lewis blood group was determined by serology. Conventional risk factors (age, gender, BMI, blood pressure, lipid profile, smoking habit) did not differ among Lewis phenotypes. However, markers of inflammation (WBC, hs-CRP, ESR) were significantly elevated and rheological parameters (RBC aggregation, plasma viscosity) were abnormal in Lewis negative subjects, especially when compared to the Le(a−b+) group.
With a prevalence of 33% in select populations, our data support the hypothesis that Le(a−b−) represents a pro-inflammatory phenotype that may contribute to the elevated cardiovascular risk in this group.
PMCID: PMC4331217  PMID: 25626016
Lewis negative phenotype; atherosclerosis; inflammation; blood rheology
Background and Purpose
Carotid atherosclerosis is a risk factor for cerebrovascular disease in older adults. Although age-related cognitive decline has been associated with cerebrovascular disease, not much is known about the consequences of carotid atherosclerosis on longitudinal cognitive function. This study examines the longitudinal relationship between atherosclerosis and cognition in a sample of non-demented older subjects using baseline measurements of carotid intima media thickness (CIMT) and annual cognitive measures of executive function (EXEC) and verbal memory (MEM).
Baseline measurements included CIMT derived from B-mode carotid artery ultrasound, structural T1-weighted images of white matter hypointensities (WMH), white matter lesions (WML) and cerebral infarct. Hypertension, low-density lipoprotein (LDL), diabetes and waist to hip ratios (WHR) were included as covariates in our models to control for cerebrovascular risks and central adiposity. Annual composite scores of EXEC and MEM functions were derived from item response theory. Linear mixed models were used to model longitudinal cognitive change.
A significant inverse relationship was found between baseline CIMT and annual EXEC score, but not annual MEM score. Subjects included in the highest 4th quartile of CIMT showed a rate of annual decline in EXEC score that was significant relative to subjects in lower quartile groups (p<0.01). The relationship between the 4th quartile of CIMT and annual EXEC score remained significant after independently adjusting for imaging measures of white matter injury and cerebral infarct.
Older adult subjects with the highest index of CIMT showed an annual decline in EXEC scores that was significant relative to subjects with lower quartile measurements of CIMT, independent of our measures of white matter injury and cerebral infarct. Our findings suggest elevated measures of CIMT may mark an atherosclerotic state, resulting in decline in executive function and not memory in non-demented older adults.
PMCID: PMC4303029  PMID: 25502351
Aging; Longitudinal Cohort Study; Carotid Intima-Media Thickness; Cognition; Magnetic Resonance Imaging
16.  Retinal Microvascular Abnormalities and Cognitive Function in Latino Adults in Los Angeles 
Ophthalmic epidemiology  2012;19(3):127-136.
Retinal vessels may provide a readily accessible surrogate approach to study vascular disease in brain small vessels. Previous epidemiologic studies of retinal microvascular abnormalities and cognition have not included large numbers of Latinos who have a high prevalence of diabetes and hypertension.
We used data from 809 elderly Latino participants in the Los Angeles Latino Eye Study (LALES) to assess whether retinal vessel caliber and microvascular abnormalities are cross-sectionally associated with lower cognitive function. Cognitive screening was conducted with the Cognitive Abilities Screening Instrument-Short form (CASI-S) and in-depth testing with the Spanish English Neuropsychological Assessment Scales (SENAS). Retinal photographs were used to identify retinopathy signs and measure retinal vessel caliber.
A total of 65.8% had high blood pressure, 34.5% had diabetes; self-reported diagnoses of heart attack, heart failure, angina and stroke were rare. Retinal calibers and any retinopathy were not associated with the CASI-S, total SENAS or any SENAS cognitive factors assessed as continuous variables. The odds of a low CASI-S score were two times higher in subjects with generalized arteriolar narrowing (OR = 2.04, 95% CI = 1.14, 3.66), and one and half times as high in those with both generalized arteriolar narrowing and retinopathy signs (OR = 1.49, 95% CI = 0.47, 4.75) though this result was based on only four cases with both risk factors and confidence limits were wide and included the null.
Retinal microvasculature imaging may provide insights into small blood vessel influences on cognition in Latino populations. Additional studies in diverse populations and prospective settings are needed.
PMCID: PMC3598630  PMID: 22568425
Epidemiology; Cognition; Retina; Latinos; Microvasculature
17.  T-cell Activation, Both Pre- and Post-HAART Levels, Correlates with Carotid Artery Stiffness over 6.5 years among HIV-infected Women in the WIHS 
T-cell activation is a major pathway driving HIV disease progression. Little is known regarding the impact of T-cell activation on HIV-associated atherosclerosis and cardiovascular disease, a common co-morbidity in HIV infection. We hypothesized that T-cell activation will predict vascular stiffness, a measure of subclinical atherosclerosis.
Linear regression models evaluated the covariate-adjusted association of T-cell activation with vascular stiffness.
CD38 and HLA-DR expression on CD4+ and CD8+ T-cells was assessed by flow cytometry among 59 HIV-negative and 376 HIV-infected (185 hepatitis-C co-infected) women in the Women's Interagency HIV Study (WIHS). T-cell activation was defined by CD8+CD38+DR+ and CD4+CD38+DR+. Multiple activation assessments over 6.5 years were averaged. In 140 women, T-cell activation was measured before and after HAART initiation. Carotid artery ultrasounds were completed a median of 6.5 years after last measurement of T- cell activation and carotid artery stiffness including distensibility and elasticity were calculated.
Percentages of CD4+ and CD8+ T-cell activation were significantly higher in HIV- infected compared to HIV-negative women. Among HIV-negative women, T-cell activation was not associated with carotid artery stiffness. Among HIV-infected women, higher CD4+ T-cell activation significantly predicted increased arterial stiffness independent of CD4 cell count and HIV RNA. The association was stronger among HIV/HCV co-infected compared to HIV-mono- infected women; however, the difference was not statistically significant (p-for interaction>0.05). Pre- and post-HAART levels of CD4+ T-cell activation significantly predicted carotid artery stiffness.
Persistent T-cell activation, even after HAART initiation, can contribute to structural and/or functional vascular damage accelerating atherogenesis in HIV infection. These results need to be confirmed in a longitudinal prospective study.
PMCID: PMC4197806  PMID: 25314253
T-cell activation; arterial stiffness; HIV-infection
18.  Physical Activity and Sex Hormone Levels in Estradiol- and Placebo-Treated Postmenopausal Women 
Menopause (New York, N.Y.)  2011;18(10):1079-1086.
Postmenopausal changes in the hormonal milieu in women with or without hormone therapy (HT) are hypothesized to be the pathway for a number of menopause-associated modifications in physiology and disease risk. Physical activity may modify these changes in women’s hormone profiles. The crucial yet complex relationship between physical activity and physiologic and pharmacologic sex hormone levels in postmenopausal women has not been investigated sufficiently.
Using structured recall, physical activity was assessed longitudinally over two years in 194 postmenopausal women (90 randomized to daily 1 mg 17β-estradiol and 104 to placebo) in the Estrogen in the Prevention of Atherosclerosis Trial. Levels of physical activity were correlated to serum sex hormone and serum hormone-binding globulin (SHBG) levels in each treatment group.
In placebo-treated women, total energy expenditure was positively associated with sex hormone-binding globulin (SHBG) (p<0.001) and inversely associated with testosterones (total, bioavailable, free) and androstenedione (p<0.001 for all), as well as with estradiol (p=0.02). In estradiol-treated women, estradiol levels were inversely associated with total energy expenditure (p=0.002) and weekly hours spent in moderate or more vigorous physical activity (p=0.001).
Physical activity is associated with lower serum levels of estradiol in both HT-treated and untreated women. In placebo-treated women only, physical activity is associated with reduced androgen levels and elevated SHBG levels.
PMCID: PMC3183237  PMID: 21646925
Physical activity; sex hormones; estradiol; menopause
19.  Clusterin Seals the Ocular Surface Barrier in Mouse Dry Eye 
PLoS ONE  2015;10(9):e0138958.
Dry eye is a common disorder caused by inadequate hydration of the ocular surface that results in disruption of barrier function. The homeostatic protein clusterin (CLU) is prominent at fluid-tissue interfaces throughout the body. CLU levels are reduced at the ocular surface in human inflammatory disorders that manifest as severe dry eye, as well as in a preclinical mouse model for desiccating stress that mimics dry eye. Using this mouse model, we show here that CLU prevents and ameliorates ocular surface barrier disruption by a remarkable sealing mechanism dependent on attainment of a critical all-or-none concentration. When the CLU level drops below the critical all-or-none threshold, the barrier becomes vulnerable to desiccating stress. CLU binds selectively to the ocular surface subjected to desiccating stress in vivo, and in vitro to the galectin LGALS3, a key barrier component. Positioned in this way, CLU not only physically seals the ocular surface barrier, but it also protects the barrier cells and prevents further damage to barrier structure. These findings define a fundamentally new mechanism for ocular surface protection and suggest CLU as a biotherapeutic for dry eye.
PMCID: PMC4581869  PMID: 26402857
20.  Tear Cathepsin S–A Candidate Biomarker for Sjögren's Syndrome 
The diagnosis of Sjögren's Syndrome (SS) in routine practice is largely a clinical one and requires a high index of suspicion by the treating physician. This great dependence upon clinical judgment frequently leads to delayed diagnosis or misdiagnosis. Tear protein profiles have been proposed as simple and reliable biomarkers for SS diagnosis. Given that cathepsin S activity is increased in the lacrimal glands and tears of NOD mice (a murine model of SS), we explored the clinical utility of using tear cathepsin S (CTSS) activity as a biomarker for SS.
A method to measure CTSS activity in tears eluted from Schirmer's strips was developed and validated. Schirmer's tests and CTSS activity measurements were performed on 278 female subjects, including patients with SS (n=73), rheumatoid arthritis (n=79), systemic lupus erythematosus (n=40), blepharitis (n=10), non-specific dry eye (n=31), or other autoimmune diseases (n=12), along with 33 healthy controls.
Median tear CTSS activity in SS patients was 4.1-fold higher than in patients with non-SS autoimmune diseases, 2.1-fold higher than in patients with non-specific dry eye, and 41.1-fold higher than in healthy controls. Tear CTSS levels were equally elevated in primary and secondary SS independent of the Schirmer's strip values or of circulating anti-SSA or anti-SSB autoantibodies.
Markedly high levels of tear CTSS activity are suggestive of SS. CTSS activity in tears can be measured in a simple, quick, economical, and non-invasive fashion and may serve as a novel biomarker and indicator of autoimmune dacryoadenitis during the workup for SS.
PMCID: PMC4077975  PMID: 24644101
21.  Subclinical Atherosclerosis is Weakly Associated with Lower Cognitive Function in Healthy Hyperhomocysteinemic Adults without Clinical Cardiovascular Disease 
Atherosclerosis is the most common pathologic process underlying cardiovascular disease (CVD). It is not well known whether subclinical atherosclerosis is an independent risk factor for lower cognitive function among individuals without clinically evident CVD.
We examined cross-sectional associations between subclinical atherosclerosis and cognitive function in a community-based sample of otherwise healthy adults with plasma homocysteine ≥8.5 µmol/L enrolled in the BVAIT study (n=504, mean age 61 years). Carotid artery intima-media thickness (CIMT), coronary (CAC) and abdominal aortic calcium (AAC) were used to measure subclinical atherosclerosis. Cognitive function was assessed with a battery of neuropsychological tests. A principal components analysis was used to extract five uncorrelated cognitive factors from scores on individual tests, and a measure of global cognition was derived. Multivariable linear regression was used to examine the association between subclinical atherosclerosis and cognitive function, adjusting for other correlates of cognition.
Increasing thickness of CIMT was associated with significantly lower scores on the verbal learning factor (β = −0.07 per 0.1 mm increase CIMT [SE(β)=0.03], p=0.01). CAC and AAC were not individually associated with any of the cognitive factors.
This study provides evidence that increasing CIMT is weakly associated with lower verbal learning abilities but not global cognition in a population of otherwise healthy middle-to-older aged adults with elevated plasma homocysteine but without clinically evident CVD. The association between CIMT and poor verbal learning may pertain particularly to men.
PMCID: PMC2661006  PMID: 18836986
cognitive function; atherosclerosis; cardiovascular disease; memory; verbal learning
22.  Mildly Elevated TSH and Cognition in Middle-Aged and Older Adults 
Thyroid  2009;19(2):111-117.
It is accepted that markedly elevated thyroid-stimulating hormone (TSH) levels are associated with impaired cognitive function. However, the findings regarding the association between mildly elevated TSH levels and cognition are equivocal. The objective of this study was to assess the relation between TSH levels in the normal to mildly elevated range (0.3–10.0 mIU/L) and several domains of cognitive function.
A healthy, community-based sample of 489 men and women (40–88 years old, mean = 60.5 years) enrolled in the B-Vitamin Atherosclerosis Intervention Trial were studied. A neuropsychological test battery was used to assess a broad array of cognitive functions. Four uncorrelated neuropsychological factors were extracted by principal component analysis. Using multivariable linear regression, performance on each factor was examined in relation to TSH levels, controlling for age, gender, race-ethnicity, education, homocysteine levels, low-density lipoprotein cholesterol levels, and smoking status.
TSH levels were not associated with any of the four factor scores in the total sample or in younger (age < 60) or older (age ≥ 60) subjects, although there was a trend for older subjects with higher levels of TSH to do more poorly on paragraph recall (p = 0.06). Gender-stratified analyses showed that TSH was positively associated with scores on word list learning for females only (p = 0.003).
In this community-based sample of middle-aged to older individuals, increasing TSH levels were not associated with significantly reduced cognitive performance in any domain. Further exploration of the effects of gender on the association between TSH and cognition is warranted.
PMCID: PMC2715222  PMID: 19191743
23.  Nevirapine Concentration in Hair Samples Is a Strong Predictor of Virologic Suppression in a Prospective Cohort of HIV-Infected Patients 
PLoS ONE  2015;10(6):e0129100.
Effective antiretroviral (ARV) therapy depends on adequate drug exposure, yet methods to assess ARV exposure are limited. Concentrations of ARV in hair are the product of steady-state pharmacokinetics factors and longitudinal adherence. We investigated nevirapine (NVP) concentrations in hair as a predictor of treatment response in women receiving ARVs. In participants of the Women’s Interagency HIV Study, who reported NVP use for >1 month from 2003–2008, NVP concentrations in hair were measured via liquid-chromatography-tandem mass-spectrometry. The outcome was virologic suppression (plasma HIV RNA below assay threshold) at the time of hair sampling and the primary predictor was nevirapine concentration categorized into quartiles. We controlled for age, race/ethnicity, pre-treatment HIV RNA, CD4 cell count, and self-reported adherence over the 6-month visit interval (categorized ≤ 74%, 75%–94% or ≥ 95%). We also assessed the relation of NVP concentration with changes in hepatic transaminase levels via multivariate random intercept logistic regression and linear regression analyses. 271 women contributed 1089 person-visits to the analysis (median 3 of semi-annual visits). Viral suppression was least frequent in concentration quartile 1 (86/178 (48.3%)) and increased in higher quartiles (to 158/204 (77.5%) for quartile 4). The odds of viral suppression in the highest concentration quartile were 9.17 times (95% CI 3.2–26, P < 0.0001) those in the lowest. African-American race was associated with lower rates of virologic suppression independent of NVP hair concentration. NVP concentration was not significantly associated with patterns of serum transaminases. Concentration of NVP in hair was a strong independent predictor of virologic suppression in women taking NVP, stronger than self-reported adherence, but did not appear to be strongly predictive of hepatotoxicity.
PMCID: PMC4460031  PMID: 26053176
24.  Metabolic Syndrome and Cognitive Function in Healthy Middle-Aged and Older Adults without Diabetes 
Few studies have addressed whether the metabolic syndrome (MetS) and its individual components are associated with cognitive function in middle-aged and older populations, as well as whether specific areas of cognition are more affected than others. We examined the cross-sectional association between MetS and six areas of cognitive function in healthy cognitively intact adults without diabetes (n = 853, mean age 61 years) randomized in two intervention trials.
The National Cholesterol Education Program (NCEP) criteria were used to identify subjects with MetS. Cognitive function was assessed with a neuropsychological battery. A principal components analysis was used to extract five uncorrelated factors interpreted to represent five areas of cognition, and a measure of global cognition was calculated.
MetS was weakly but non-significantly associated with lower verbal learning (β=−.14 [SE(β) = 0.09], p = .15). As the number of MetS criteria increased, scores on global cognition (p trend = .01), verbal learning (p trend = .06) and semantic memory (p trend = .04) decreased. Hypertension was the only MetS risk factor that was independently correlated with lower verbal learning (β = −.17 [SE(β) = 0.08], p = .04), semantic memory (β = −.26 [SE(β) = 0.08], p = .001) and global cognition (β = −.15 [SE(β) = 0.07], p = .04).
This study adds to the evidence of an association between MetS and lower cognitive function among healthy middle-aged and older adults without CVD and diabetes, as well as confirms the correlation between hypertension and lower cognition.
PMCID: PMC2742696  PMID: 18608045
Metabolic syndrome; Cognitive function; Hypertension; Memory; Verbal learning; Global cognition
25.  Mildly Elevated TSH and Cognition in Middle-Aged and Older Adults 
It is accepted that markedly elevated thyroid-stimulating hormone (TSH) levels are associated with impaired cognitive function. However, the findings regarding the association between mildly elevated TSH levels and cognition are equivocal. The objective of this study was to assess the relation between TSH levels in the normal to mildly elevated range (0.3–10.0 mIU/L) and several domains of cognitive function.
A healthy, community-based sample of 489 men and women (40–88 years old, mean=60.5 years) enrolled in the B-Vitamin Atherosclerosis Intervention Trial were studied. A neuropsychological test battery was used to assess a broad array of cognitive functions. Four uncorrelated neuropsychological factors were extracted by principal component analysis. Using multivariable linear regression, performance on each factor was examined in relation to TSH levels, controlling for age, gender, race-ethnicity, education, homocysteine levels, low-density lipoprotein cholesterol levels, and smoking status.
TSH levels were not associated with any of the four factor scores in the total sample or in younger (age<60) or older (age≥60) subjects, although there was a trend for older subjects with higher levels of TSH to do more poorly on paragraph recall ( p = 0.06). Gender-stratified analyses showed that TSH was positively associated with scores on word list learning for females only ( p=0.003).
In this community-based sample of middle-aged to older individuals, increasing TSH levels were not associated with significantly reduced cognitive performance in any domain. Further exploration of the effects of gender on the association between TSH and cognition is warranted.
PMCID: PMC2715222  PMID: 19191743

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